Epstein-Barr-positive classical Hodgkin lymphoma-associated haemophagocytic lymphohistocytiosis: a rare case

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, which is usually triggered by autoimmune disorders, viral infections and malignancy, like lymphomas. We present a 60-year-old Hispanic woman with a medical history of hypertension and systemic lupus erythematosus presenting with fever, generalised weakness and shortness of breath for 3 weeks. She was hypotensive on presentation, and a CT scan of abdomen/chest showed multiple irregular hepatic and splenic hypodense lesions. A liver biopsy revealed Classical Hodgkin lymphoma (cHL) with positive Epstein-Barr virus (EBV) staining that was later confirmed with high serum EBV DNA levels. Incidentally, a liver biopsy disclosed haemophagocytosis in some cells. HLH-associated cHL is an uncommon condition that can cause severe systemic symptoms acting as the perfect mimic of septic shock, deviating the clinical eye toward treating with antibiotics and not addressing in a timely manner the real aetiology of the patient’s condition.

Background

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, which is usually triggered by autoimmune disorders, viral infections and malignancy, like lymphomas.¹ Association of HLH with classical Epstein-Barr virus (EBV)-positive Hodgkin’s lymphoma L is rare.² We present a case where patient who came with overt septic and cardiogenic shock required multiple treatments and was later found to have Classical Hodgkin lymphoma (cHL) and HLH, both proven by a biopsy. cHL-associated HLH is an uncommon condition that can cause severe systemic symptoms acting as the perfect mimic of septic shock, deviating the clinical eye toward treating with antibiotics and not addressing in a timely manner the real aetiology of the patient’s condition. HLH should always be present in differentials, especially if the patient has any history of well-known triggers or malignancy after excluding common causes of septic shock or other more uncommon causes like macrophage activation syndrome (MAS) and atypical haemolytic uraemic syndrome (aHUS).

Case presentation

A 60-year-old Hispanic woman with a medical history of hypertension (HTN) and systemic lupus erythematosus (SLE), treated with a short course of methotrexate more than a year prior to admission, came to the emergency room with complaints of fever, generalised weakness and shortness of breath 3 weeks prior to presentation. Physical examination disclosed accessory muscle use with bi-basilar crackles on lung examination and bilateral +2 pitting lower extremity oedema. On admission, she was hypotensive (68/43 mm Hg), tachycardic (118 beats per minutes) with fever of 102.2 F and hypoxic (SpO₂84%) on room air. Initial working diagnosis was septic shock, and patient was given 30 mL/kg bolus of crystalloid and broad-spectrum antibiotics with no resolution of the hypotension, thus requiring initiation of three vasoactive drips and support with non-invasive mechanical ventilation due to hypoxic respiratory failure. On initial laboratory data, shown in table 1, she was found to be pancytopaenic and hyperlactidaemic. Chest X-ray (CXR) showed bilateral ground glass infiltrates. Infectious diseases (ID), Cardiology, Rheumatology and haemato/oncology consultations were obtained to help with the patient management and rule out other causes.

Table 1.

Admission laboratory data

Study	Value	Normal values
White blood cell count, ×103/µL	1.4	4.8–10.8
Haemoglobin, g/dL	10.6	12–16
Platelets, ×103/µL	55	130–400
BUN, mg/dL	19	7–20
Creatinine, mg/dL	0.9	0.6–1.2
CO2, meq/L	17	20–29
Creatine kinase, U/L	1099	<206
AST, U/L	123	3–38
ALT, U/L	61	≤49
Alkaline phosphatase, U/L	153	41–107
Total bilirubin, mg/dL	2.1	0–1.2
Lactic acid, mmol/L	4.62	0.5–2.2
Troponin I, ng/mL	1.3	0.00–0.08
Creatine kinase-MB, ng/mL	3.1	≤6.6
B-Type natriuretic peptide, pg/mL	<10.1	10.0–100.0

Patient’s clinical data.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen.

She remained hypotensive and later developed pulmonary oedema that required emergent intubation. Transthoracic echocardiogram (TTE) revealed left ventricular ejection fraction of 15%–20% with global wall motion abnormalities. She had to be started on an intra-aortic balloon pump. Later, the patient developed acute tubular necrosis (ATN), and her serum creatinine increased to 6.7 mg/dL, with associated decrease in urine output requiring intermitted haemodialysis. Table 2 summarises autoimmune and ID panel, which showed hypocomplementaemia with decreased complement activity and positive single-stranded DNA that were non-specific as per the rheumatology and haemato/oncology services. CT scan of the abdomen and chest showed multiple irregular hepatic and splenic hypodense lesions, moderate splenomegaly and para-aortic lymphadenopathy (figure 1). Serum Coxsackie virus type B3 antibody, done on admission, showed a level of 1:20, and convalescent titre increased to 1:160 at day 15, suggestive of Coxsackie virus B3 myocarditis. Re-consultation to haematology service was obtained, and a bone marrow biopsy was performed showing no evidence of disease, and with a working diagnosis of HLH, complementary laboratory data showed hyperferritinaemia, increased interleukin-2 (IL-2) receptor (CD-25), hypertriglyceridaemia and elevated lactate dehydrogenase (table 3).

Table 2.

Autoimmune, bacterial and viral serology

Study	Value	Normal values
CH50	27	60–124
C3, mg/dL	34	88–201
C4, mg/dL	26	10–40
Single-stranded DNA	Positive	Negative
Antinuclear antibodies	Negative	Negative
PCR respiratory panel	Negative	Negative
Acute viral hepatitis panel	Negative	Negative
HIV	Negative	Negative
Cytomegalovirus by PCR	Negative	Negative

Patient’s clinical data.

Figure 1.

(A) Yellow arrow pointing to a liver lesion in sagittal cut on CT abdomen. (B) Yellow arrow pointing to multiple splenic lesions. (C) Yellow arrow pointing multiple liver lesions on coronal cut of CT abdomen. Red arrow pointing to para-aortic lymphadenopathy.

Table 3.

HLH serology

Study	Value	Normal values
Ferritin, ng/mL	14 863	10–120
IL-2 soluble (CD-25), pg/mL	13 190	<1033
Triglyceride, mg/dL	288	<150
Fibrinogen, mg/dL	97	200–540
LDH, U/L	7853	117–229

Patient’s clinical data.

IL-2, interleukin-2; LDH, lactate dehydrogenase.

Serum EBV DNA level by PCR was 50 100 copies/mL, and taking into consideration the liver findings on CT, a biopsy was obtained disclosing classical Hodgkin’s lymphoma with EBV virus positive (figure 2), revealing haemophagocytosis in liver histiocytes (figure 3).

Figure 2.

(A): Positive CD-45 cells in a liver biopsy (×1000). (B) Positive CD-30 cells in a liver biopsy (×1000). (C) Positive CD-15 cells in a liver biopsy (×1000). (D) EBV (+) cells (×100). EBV, Epstein-Barr virus.

Figure 3.

(A): Large cell with hyperchromatic nuclei (arrow) (histiocyte), 1000×. (B–D) Arrow pointing to histiocystes with erythrocytes inside (haemophagocytosis), 1000×. (E) Reed-Sternberg cell (Circle) with surrounding haemophagocytosis (arrow), 1000×.

She met clinical and pathological criteria of HLH, including fever, splenomegaly, pancytopaenia, hypofibrinogen, elevated serum ferritin, triglycerides and CD-25 level and the presence of haemophagocytosis in the liver. Due to multiorgan failure, she was not a candidate for immediate chemotherapy for Hodgkin’s lymphoma, and family decided to request hospice consultation for comfort care per patient wishes on hospital day 24. Final diagnosis was made: classical EBV-positive Hodgkin’s lymphoma associated with HLH.

Investigations

Chest X-ray on admission

1. Moderate diffuse alveolar infiltrates, left greater than right.

CT abdomen and pelvis without contrast

1. There are moderate bilateral pleural fluid collections.

2. Multiple micronodules in the liver and spleen consistent with metastatic disease versus infectious process. Mild to moderate splenomegaly.

3. Mild four-quadrant ascites.

4. There is gallbladder wall thickening consistent with cholecystitis versus right heart failure versus hepatitis versus pancreatitis.

5. Para-aortic adenopathy.

6. Abnormal 1.5×2.0 cm right iliac bifurcation lymph node. Reactive versus neoplastic.

Bone marrow biopsy

1. Extremely hypocellular marrow (much less than 5% cellularity) demonstrating rare haematopoetic precursors without neoplastic features.

2. No evidence of lymphoma or haemophagocytosis present in this specimen.

3. Iron stain performed on the bone marrow biopsy does not demonstrate any stainable marrow iron stores.

4. No flow cytometric immunophenotypic abnormalities detected (see report).

Liver biopsy

1. Rather severe congested hepatopathy with zones of hepatocyte loss.

2. Widespread inflammation of portal tracts with occasional histiocytes appearing to possibly contain red few blood cells.

3. Infiltrate of large cells with hyperchromatic irregular and sometimes multilobated nuclei, some with prominent eosinophilic nucleoli (consistent with Classical Hodgkin lymphoma).

4. Inmunohistochemical stains: large cells are positive for CD-30, CD-15 and PAX-5, and negative for CD-3, CD-20, CD-45, ADV, CMV and HSVI+II.

5. Positive for EBV by in situ hybridisation.

6. Moderate macrovesicular and microvesicular steatosis.

7. Mild to moderate haemosiderosis.

Coxsackie virus type B3 antibody

1. 1:160

Differential diagnosis

• Septic shock.

• Cardiogenic shock.

• Invasive fungal disease (Aspergillus/Coccicoidomycosis).

• Shock liver.

• Acute hepatitis.

• MAS.

• aHUS.

Treatment

The patient underwent multiple symptomatic treatments, but given her critical clinical condition and Karnofsky performance status of 20–10 (ECOG: 4), she was not a candidate for chemotherapy for Hodgkin lymphoma, and pulse steroids for HLH were not given, honouring patient wishes executed by family members, who requested hospice consult.

Outcome and follow-up

After giving the final diagnosis to the family and explaining the next course of action of providing pulse steroid for the treatment of HLH and further improvement of the clinical picture, allowing the patient to improve and become a candidate for chemotherapy in the future, family decided to honour patient wishes and requested hospice consultation. Comfort measures were initiated and terminal extubation performed. The patient passed away 4 hours postextubation.

Discussion

HLH is a life-threatening condition resulting from uncontrolled activation of immune cells (macrophages, lymphocyte and histiocytes) that leads to a hyperinflammatory state, releasing an elevated number of cytokines into the blood stream, which stimulates these immune cells to engulf normal cells. Pathogenesis in not well described, but multiple conditions can serve as a trigger, such as inherited genetic mutations, autoimmune disorders, viral infections and malignancy, like lymphoma, specifically T cell/NK cell and diffuse large B-cell lymphoma accounting for 65% of cases together and cHL, accounting only for 6.3% of cases.^1–3

The Histiocyte society established specific diagnostic criteria in 2004 that were later revised in 2008 (box 1); our patient underwent analysis and ended up fulfilling six of the eight criteria, but interestingly, the bone marrow biopsy did not show any evidence of HLH or cHL invasion but in one of the extramedullary organs where HLH can be present and still be diagnostic.⁴ The association of Hodgkin lymphoma and EBV is well known and has a prevalence as high as 53% of all the Hodgkin lymphomas; this is without discriminating between cHL and nodular type Hodgkin lymphoma.⁵

Box 1. Diagnostic criteria for HLH according to the HLH 2004 trial.

• Molecular diagnosis consistent with HLH:

  • Pathological mutations on: PRFI, UNCI 3D, RAB27A, STX I I, SH2D IA, XIAP

• Fever (>38.5 C)

• Splenomegaly

• Cytopaenias (affecting two of the three lines):

  • Haemoglobin <9 g/dL

  • Platelets <100.000/µL

  • Absolute neutrophilic count <1000 per µL

• Hypertriglyceridaemia

• HLH on bone marrow, lymph nodes, spleen or liver

• Low or absent natural killer cell activity

• Ferritin level >500 ng/mL

• Elevated soluble IL-2 receptor (CD-25)

Our patient presented with overt septic and cardiogenic shock, requiring multiple vasoactive drug support and further balloon pump treatment; clear aetiology of the acute condition was not able to be established. CT scan showed multiple liver and splenic masses, and the biopsy was consistent with cHL with positive EBV staining that was later confirmed with high serum EBV DNA levels. Incidentally, the liver biopsy disclosed haemophagocytosis in some cells; the association of HLH with cHL has been rarely reported, but patient’s clinical picture matched with HLH clinical course, after ruling out other causes like MAS due to the patient presentation and medical history.^{6 7}

Only hypotheses can be made when trying to find a specific trigger for HLH in our patient, but given the well-known association of lymphoma with HLH and the fact that the patient was diagnosed with EBV (+) cHL, we conclude that in this specific case, the underlying lymphoma acted as trigger for HLH, and Coxsackie B3 viral coinfection was an incidental complication.

Learning points.

• Septic shock, although the most common cause of admission to the intensive care unit, is not always the answer of shock. We, as clinicians, should always test and rule out other rare causes with the help of a multidisciplinary team if available.

• Haemophagocytic lymphohistiocytosis (HLH) can manifest after multiple triggers, such as infections, neoplastic (B-cell or T-cell lymphomas). It is a rare condition, but sometimes is overlooked.

• As per HLH 2004 Trial diagnostic criteria, HLH diagnosis can be made without proof of haemophagocytosis in the bone marrow, but also in extramedullary organs, like spleen, and in our case, liver.

• It is challenging to differentiate between whether a patient may have actually HLH or HLH-like illness, such as macrophage activation syndrome and atypical haemolytic uraemic syndrome, in the settings of severe infection, autoimmune disease or neoplastic disease like in the presented case.

• In patients with underlying conditions, like neoplasm, HLH may develop as result of rapidly progressing disease, which may be the case in our patient.

• HLH is a perfect mimicking type of disease due to the way it presents especially in the critical ill patient, where it can simulate many other conditions or syndromes. It is our intention to trigger clinicians to think of HLH when confronted with patients with refractory shock, worsening sepsis, pancytopaenia, hyperferritinaemia and hepatosplenomegaly.